Correlation between RPPA expression and clinical features
Kidney Renal Papillary Cell Carcinoma (Primary solid tumor)
28 January 2016  |  analyses__2016_01_28
Maintainer Information
Citation Information
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Correlation between RPPA expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1KW5FGV
Overview
Introduction

This pipeline uses various statistical tests to identify RPPAs whose expression levels correlated to selected clinical features. The input file "KIRP-TP.rppa.txt" is generated in the pipeline RPPA_AnnotateWithGene in the stddata run.

Summary

Testing the association between 195 genes and 12 clinical features across 215 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 9 clinical features related to at least one genes.

  • 30 genes correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • ANXA7 |ANNEXIN_VII ,  YWHAE|14-3-3_EPSILON ,  AR|AR ,  SMAD4|SMAD4 ,  FN1|FIBRONECTIN ,  ...

  • 30 genes correlated to 'YEARS_TO_BIRTH'.

    • RPS6KB1|P70S6K_PT389 ,  SCD1|SCD1 ,  BECN1|BECLIN ,  NRAS|N-RAS ,  PECAM1|CD31 ,  ...

  • 30 genes correlated to 'PATHOLOGIC_STAGE'.

    • CTNNB1|ALPHA-CATENIN ,  CCNB1|CYCLIN_B1 ,  FN1|FIBRONECTIN ,  CLDN7|CLAUDIN-7 ,  YWHAE|14-3-3_EPSILON ,  ...

  • 30 genes correlated to 'PATHOLOGY_T_STAGE'.

    • CTNNB1|ALPHA-CATENIN ,  FN1|FIBRONECTIN ,  VHL|VHL ,  CCNB1|CYCLIN_B1 ,  CLDN7|CLAUDIN-7 ,  ...

  • 30 genes correlated to 'PATHOLOGY_N_STAGE'.

    • FN1|FIBRONECTIN ,  MSH6|MSH6 ,  VHL|VHL ,  CTNNB1|ALPHA-CATENIN ,  CLDN7|CLAUDIN-7 ,  ...

  • 26 genes correlated to 'PATHOLOGY_M_STAGE'.

    • CTNNB1|ALPHA-CATENIN ,  FASN|FASN ,  YWHAE|14-3-3_EPSILON ,  TFRC|TFRC ,  FOXO3|FOXO3A_PS318_S321 ,  ...

  • 28 genes correlated to 'GENDER'.

    • PDK1|PDK1 ,  YWHAE|14-3-3_EPSILON ,  RICTOR|RICTOR ,  MSH6|MSH6 ,  ANXA7 |ANNEXIN_VII ,  ...

  • 13 genes correlated to 'KARNOFSKY_PERFORMANCE_SCORE'.

    • MAP2K1|MEK1 ,  ANXA1|ANNEXIN-1 ,  GAB2|GAB2 ,  EIF4EBP1|4E-BP1 ,  CTNNB1|ALPHA-CATENIN ,  ...

  • 1 gene correlated to 'ETHNICITY'.

    • RB1|RB_PS807_S811

  • No genes correlated to 'NUMBER_PACK_YEARS_SMOKED', 'YEAR_OF_TOBACCO_SMOKING_ONSET', and 'RACE'.

Results
Overview of the results

Complete statistical result table is provided in Supplement Table 1

Table 1.  Get Full Table This table shows the clinical features, statistical methods used, and the number of genes that are significantly associated with each clinical feature at P value < 0.05 and Q value < 0.3.

Clinical feature Statistical test Significant genes Associated with                 Associated with
DAYS_TO_DEATH_OR_LAST_FUP Cox regression test N=30   N=NA   N=NA
YEARS_TO_BIRTH Spearman correlation test N=30 older N=22 younger N=8
PATHOLOGIC_STAGE Kruskal-Wallis test N=30        
PATHOLOGY_T_STAGE Spearman correlation test N=30 higher stage N=14 lower stage N=16
PATHOLOGY_N_STAGE Spearman correlation test N=30 higher stage N=14 lower stage N=16
PATHOLOGY_M_STAGE Wilcoxon test N=26 class1 N=26 class0 N=0
GENDER Wilcoxon test N=28 male N=28 female N=0
KARNOFSKY_PERFORMANCE_SCORE Spearman correlation test N=13 higher score N=8 lower score N=5
NUMBER_PACK_YEARS_SMOKED Spearman correlation test   N=0        
YEAR_OF_TOBACCO_SMOKING_ONSET Spearman correlation test   N=0        
RACE Kruskal-Wallis test   N=0        
ETHNICITY Wilcoxon test N=1 not hispanic or latino N=1 hispanic or latino N=0
Clinical variable #1: 'DAYS_TO_DEATH_OR_LAST_FUP'

30 genes related to 'DAYS_TO_DEATH_OR_LAST_FUP'.

Table S1.  Basic characteristics of clinical feature: 'DAYS_TO_DEATH_OR_LAST_FUP'

DAYS_TO_DEATH_OR_LAST_FUP Duration (Months) 0.1-194.8 (median=25.2)
  censored N = 182
  death N = 32
     
  Significant markers N = 30
  associated with shorter survival NA
  associated with longer survival NA
List of top 10 genes differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of top 10 genes significantly associated with 'Time to Death' by Cox regression test. For the survival curves, it compared quantile intervals at c(0, 0.25, 0.50, 0.75, 1) and did not try survival analysis if there is only one interval.

logrank_P Q C_index
ANXA7 |ANNEXIN_VII 3.01e-06 0.00059 0.283
YWHAE|14-3-3_EPSILON 1.65e-05 0.0016 0.269
AR|AR 3.81e-05 0.0025 0.358
SMAD4|SMAD4 0.000103 0.005 0.274
FN1|FIBRONECTIN 0.000162 0.0063 0.703
FASN|FASN 0.000251 0.0074 0.725
CTNNB1|ALPHA-CATENIN 0.000267 0.0074 0.245
CCNB1|CYCLIN_B1 0.000331 0.0081 0.669
MYH11|MYH11 0.00132 0.027 0.648
CAV1|CAVEOLIN-1 0.00139 0.027 0.664
Clinical variable #2: 'YEARS_TO_BIRTH'

30 genes related to 'YEARS_TO_BIRTH'.

Table S3.  Basic characteristics of clinical feature: 'YEARS_TO_BIRTH'

YEARS_TO_BIRTH Mean (SD) 61.62 (12)
  Significant markers N = 30
  pos. correlated 22
  neg. correlated 8
List of top 10 genes differentially expressed by 'YEARS_TO_BIRTH'

Table S4.  Get Full Table List of top 10 genes significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
RPS6KB1|P70S6K_PT389 0.3805 1.128e-08 2.2e-06
SCD1|SCD1 0.3234 1.589e-06 0.00012
BECN1|BECLIN 0.3165 2.712e-06 0.00012
NRAS|N-RAS 0.316 2.81e-06 0.00012
PECAM1|CD31 0.3147 3.121e-06 0.00012
ARHI|ARHI 0.3183 3.684e-06 0.00012
TP53|P53 0.3067 5.684e-06 0.000158
SMAD4|SMAD4 0.301 8.563e-06 0.000209
FOXO3|FOXO3A 0.2981 1.056e-05 0.000223
FOXM1|FOXM1 0.297 1.142e-05 0.000223
Clinical variable #3: 'PATHOLOGIC_STAGE'

30 genes related to 'PATHOLOGIC_STAGE'.

Table S5.  Basic characteristics of clinical feature: 'PATHOLOGIC_STAGE'

PATHOLOGIC_STAGE Labels N
  STAGE I 129
  STAGE II 18
  STAGE III 46
  STAGE IV 14
     
  Significant markers N = 30
List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

Table S6.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGIC_STAGE'

kruskal_wallis_P Q
CTNNB1|ALPHA-CATENIN 2.471e-09 4.82e-07
CCNB1|CYCLIN_B1 5.057e-06 0.000364
FN1|FIBRONECTIN 7.615e-06 0.000364
CLDN7|CLAUDIN-7 8.96e-06 0.000364
YWHAE|14-3-3_EPSILON 9.338e-06 0.000364
RICTOR|RICTOR 1.515e-05 0.000493
SQSTM1|P62-LCK-LIGAND 2.774e-05 0.000773
MSH6|MSH6 5.155e-05 0.00121
G6PD|G6PD 5.578e-05 0.00121
FASN|FASN 6.738e-05 0.00129
Clinical variable #4: 'PATHOLOGY_T_STAGE'

30 genes related to 'PATHOLOGY_T_STAGE'.

Table S7.  Basic characteristics of clinical feature: 'PATHOLOGY_T_STAGE'

PATHOLOGY_T_STAGE Mean (SD) 1.62 (0.88)
  N
  T1 137
  T2 25
  T3 51
  T4 2
     
  Significant markers N = 30
  pos. correlated 14
  neg. correlated 16
List of top 10 genes differentially expressed by 'PATHOLOGY_T_STAGE'

Table S8.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_T_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
CTNNB1|ALPHA-CATENIN -0.4412 1.183e-11 2.31e-09
FN1|FIBRONECTIN 0.3654 3.402e-08 3.32e-06
VHL|VHL -0.3384 3.69e-07 2.4e-05
CCNB1|CYCLIN_B1 0.3329 5.87e-07 2.86e-05
CLDN7|CLAUDIN-7 -0.3271 9.377e-07 3.66e-05
SQSTM1|P62-LCK-LIGAND 0.3133 2.796e-06 8.47e-05
G6PD|G6PD 0.3122 3.039e-06 8.47e-05
RICTOR|RICTOR 0.2967 9.605e-06 0.000234
FRAP1|MTOR_PS2448 -0.2894 1.623e-05 0.000352
EIF4G1|EIF4G 0.2834 2.459e-05 0.000479
Clinical variable #5: 'PATHOLOGY_N_STAGE'

30 genes related to 'PATHOLOGY_N_STAGE'.

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'

PATHOLOGY_N_STAGE Mean (SD) 0.38 (0.57)
  N
  N0 47
  N1 21
  N2 3
     
  Significant markers N = 30
  pos. correlated 14
  neg. correlated 16
List of top 10 genes differentially expressed by 'PATHOLOGY_N_STAGE'

Table S10.  Get Full Table List of top 10 genes significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
FN1|FIBRONECTIN 0.5769 1.399e-07 2.73e-05
MSH6|MSH6 0.5289 2.125e-06 0.000207
VHL|VHL -0.5032 7.744e-06 0.000503
CTNNB1|ALPHA-CATENIN -0.491 1.378e-05 0.000672
CLDN7|CLAUDIN-7 -0.4193 0.0002729 0.0106
ERRFI1|MIG-6 -0.4102 0.0003808 0.0111
YWHAE|14-3-3_EPSILON -0.4085 0.0004049 0.0111
ANXA7 |ANNEXIN_VII -0.4054 0.0004534 0.0111
FASN|FASN 0.3999 0.0005493 0.0119
PARK7|DJ-1 -0.3959 0.0006326 0.0123
Clinical variable #6: 'PATHOLOGY_M_STAGE'

26 genes related to 'PATHOLOGY_M_STAGE'.

Table S11.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 73
  class1 8
     
  Significant markers N = 26
  Higher in class1 26
  Higher in class0 0
List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

Table S12.  Get Full Table List of top 10 genes differentially expressed by 'PATHOLOGY_M_STAGE'

W(pos if higher in 'class1') wilcoxontestP Q AUC
CTNNB1|ALPHA-CATENIN 74 0.0005753 0.112 0.8733
FASN|FASN 486 0.002191 0.196 0.8322
YWHAE|14-3-3_EPSILON 115 0.005207 0.196 0.8031
TFRC|TFRC 469 0.005207 0.196 0.8031
FOXO3|FOXO3A_PS318_S321 116 0.005467 0.196 0.8014
ANXA7 |ANNEXIN_VII 118 0.006024 0.196 0.7979
SCD1|SCD1 122 0.007293 0.203 0.7911
RICTOR|RICTOR 457 0.009214 0.203 0.7825
MSH6|MSH6 454 0.01057 0.203 0.7774
YWHAB|14-3-3_BETA 134 0.01266 0.203 0.7705
Clinical variable #7: 'GENDER'

28 genes related to 'GENDER'.

Table S13.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 56
  MALE 159
     
  Significant markers N = 28
  Higher in MALE 28
  Higher in FEMALE 0
List of top 10 genes differentially expressed by 'GENDER'

Table S14.  Get Full Table List of top 10 genes differentially expressed by 'GENDER'. 2 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
PDK1|PDK1 6247 7.379e-06 0.00116 0.7016
YWHAE|14-3-3_EPSILON 6206 1.187e-05 0.00116 0.697
RICTOR|RICTOR 2889 9.503e-05 0.00618 0.6755
MSH6|MSH6 2992 0.0002667 0.013 0.664
ANXA7 |ANNEXIN_VII 5879 0.0003663 0.0135 0.6603
IGFBP2|IGFBP2 3093 0.0006904 0.0192 0.6526
EGFR|EGFR_PY1173 5768 0.001016 0.0248 0.6478
CLDN7|CLAUDIN-7 5739 0.001311 0.0284 0.6445
MET|C-MET_PY1235 5680 0.002168 0.0423 0.6379
CCNE1|CYCLIN_E1 3239 0.002456 0.0435 0.6362
Clinical variable #8: 'KARNOFSKY_PERFORMANCE_SCORE'

13 genes related to 'KARNOFSKY_PERFORMANCE_SCORE'.

Table S15.  Basic characteristics of clinical feature: 'KARNOFSKY_PERFORMANCE_SCORE'

KARNOFSKY_PERFORMANCE_SCORE Mean (SD) 89.14 (21)
  Significant markers N = 13
  pos. correlated 8
  neg. correlated 5
List of top 10 genes differentially expressed by 'KARNOFSKY_PERFORMANCE_SCORE'

Table S16.  Get Full Table List of top 10 genes significantly correlated to 'KARNOFSKY_PERFORMANCE_SCORE' by Spearman correlation test

SpearmanCorr corrP Q
MAP2K1|MEK1 -0.5156 3.437e-05 0.0067
ANXA1|ANNEXIN-1 0.3677 0.004519 0.191
GAB2|GAB2 -0.3629 0.005118 0.191
EIF4EBP1|4E-BP1 -0.3605 0.005445 0.191
CTNNB1|ALPHA-CATENIN 0.3555 0.006166 0.191
YWHAE|14-3-3_EPSILON 0.3523 0.006678 0.191
RAB25|RAB25 0.3466 0.007695 0.191
CAV1|CAVEOLIN-1 -0.3458 0.007848 0.191
FN1|FIBRONECTIN -0.3365 0.009791 0.212
RPS6KB1|P70S6K_PT389 0.3255 0.01265 0.247
Clinical variable #9: 'NUMBER_PACK_YEARS_SMOKED'

No gene related to 'NUMBER_PACK_YEARS_SMOKED'.

Table S17.  Basic characteristics of clinical feature: 'NUMBER_PACK_YEARS_SMOKED'

NUMBER_PACK_YEARS_SMOKED Mean (SD) 31.25 (27)
  Significant markers N = 0
Clinical variable #10: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

No gene related to 'YEAR_OF_TOBACCO_SMOKING_ONSET'.

Table S18.  Basic characteristics of clinical feature: 'YEAR_OF_TOBACCO_SMOKING_ONSET'

YEAR_OF_TOBACCO_SMOKING_ONSET Mean (SD) 1970.13 (15)
  Significant markers N = 0
Clinical variable #11: 'RACE'

No gene related to 'RACE'.

Table S19.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 6
  BLACK OR AFRICAN AMERICAN 45
  WHITE 150
     
  Significant markers N = 0
Clinical variable #12: 'ETHNICITY'

One gene related to 'ETHNICITY'.

Table S20.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 7
  NOT HISPANIC OR LATINO 177
     
  Significant markers N = 1
  Higher in NOT HISPANIC OR LATINO 1
  Higher in HISPANIC OR LATINO 0
List of one gene differentially expressed by 'ETHNICITY'

Table S21.  Get Full Table List of one gene differentially expressed by 'ETHNICITY'

W(pos if higher in 'NOT HISPANIC OR LATINO') wilcoxontestP Q AUC
RB1|RB_PS807_S811 c("161", "0.0009202") c("161", "0.0009202") 0.179 0.8701
Methods & Data
Input
  • Expresson data file = KIRP-TP.rppa.txt

  • Clinical data file = KIRP-TP.merged_data.txt

  • Number of patients = 215

  • Number of genes = 195

  • Number of clinical features = 12

Selected clinical features
  • Further details on clinical features selected for this analysis, please find a documentation on selected CDEs (Clinical Data Elements). The first column of the file is a formula to convert values and the second column is a clinical parameter name.

  • Survival time data

    • Survival time data is a combined value of days_to_death and days_to_last_followup. For each patient, it creates a combined value 'days_to_death_or_last_fup' using conversion process below.

      • if 'vital_status'==1(dead), 'days_to_last_followup' is always NA. Thus, uses 'days_to_death' value for 'days_to_death_or_fup'

      • if 'vital_status'==0(alive),

        • if 'days_to_death'==NA & 'days_to_last_followup'!=NA, uses 'days_to_last_followup' value for 'days_to_death_or_fup'

        • if 'days_to_death'!=NA, excludes this case in survival analysis and report the case.

      • if 'vital_status'==NA,excludes this case in survival analysis and report the case.

    • cf. In certain diesase types such as SKCM, days_to_death parameter is replaced with time_from_specimen_dx or time_from_specimen_procurement_to_death .

  • This analysis excluded clinical variables that has only NA values.

Survival analysis

For survival clinical features, logrank test in univariate Cox regression analysis with proportional hazards model (Andersen and Gill 1982) was used to estimate the P values comparing quantile intervals using the 'coxph' function in R. Kaplan-Meier survival curves were plotted using quantile intervals at c(0, 0.25, 0.50, 0.75, 1). If there is only one interval group, it will not try survival analysis.

Correlation analysis

For continuous numerical clinical features, Spearman's rank correlation coefficients (Spearman 1904) and two-tailed P values were estimated using 'cor.test' function in R

Wilcoxon rank sum test (Mann-Whitney U test)

For two groups (mutant or wild-type) of continuous type of clinical data, wilcoxon rank sum test (Mann and Whitney, 1947) was applied to compare their mean difference using 'wilcox.test(continuous.clinical ~ as.factor(group), exact=FALSE)' function in R. This test is equivalent to the Mann-Whitney test.

Q value calculation

For multiple hypothesis correction, Q value is the False Discovery Rate (FDR) analogue of the P value (Benjamini and Hochberg 1995), defined as the minimum FDR at which the test may be called significant. We used the 'Benjamini and Hochberg' method of 'p.adjust' function in R to convert P values into Q values.

Download Results

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

References
[1] Andersen and Gill, Cox's regression model for counting processes, a large sample study, Annals of Statistics 10(4):1100-1120 (1982)
[2] Spearman, C, The proof and measurement of association between two things, Amer. J. Psychol 15:72-101 (1904)
[3] Mann and Whitney, On a Test of Whether one of Two Random Variables is Stochastically Larger than the Other, Annals of Mathematical Statistics 18 (1), 50-60 (1947)
[4] Benjamini and Hochberg, Controlling the false discovery rate: a practical and powerful approach to multiple testing, Journal of the Royal Statistical Society Series B 59:289-300 (1995)